Na+ Channels Control Metabolism and Global Ca2+ Signaling by Inducing Na+ and Ca2+ Responses that are Propagating into the Mitochondria of Beta Cells

Naþchannels inbcells are abundantly expressed and prone to prolong activation,yet their role in regulating cellular Naþfluxes or mitochondrial Ca2þtransient,thereby metabolism is poorly understood Here, we combined fluorescent ion andelectrophysiological analysis with molecular control of transporter expressionand mitochondrial metabolism in MIN6 and primary beta cells. Glucose induceda TTX sensitive cytosolic Naþand Ca2þresponse that were propagating into themitochondria. Mitochondrial Ca2þinflux was largely blocked in cell transfectedwith siRNA of the mitochondrial Ca2þuniporter MCU. Knockdown of the mito-chondrial Naþ/Ca2þexchanger (NCLX) and Naþdose response analysis showthat NCLX is major mitochondrial Naþinflux pathway, tuned to sense cytosolicNaþchanges mediated by high glucose. TTX sensitive mitochondrial Ca2þMonday, February 17, 2014241a
Israel Sekler
response enhances mitochondrial metabolism triggered mitochondrial hyperpolar-ization and enhanced ATP production. Liþa substrate cation of NCLX but not ofNCX replace Naþin enhancing the cytosolic and mitochondrial Ca2þresponsesAltogether, our results show that combined electrical and ion flux activity ofTTX sensitive Naþchannels initiates a cytosolic Naþand Ca2þsignals propagatingby the MCU and NCLX to the mitochondria, thereby shaping cytosolic ormitochondrial Ca2þtransients and metabolism of beta cells